Protecting Group-Controlled Remote Regioselective Electrophilic Aromatic Halogenation Reactions

Abstract

Being able to utilise a protecting group to influence remote regiocontrol offers a simple alternative approach to direct late-stage functionalisation of complex organic molecules. However, protecting groups that have the ability to influence reaction regioselectivity remote to their local chemical environment are not widely reported in the literature. Herein, we report the development of remote regioselective electrophilic aromatic substitution (S E Ar) reactions that are enabled via the application of the tetrafluoropyridyl (TFP) phenol protecting group. We demonstrate that through sequential reactions and protection/deprotection of the TFP group, substitution patterns which do not conform to classical S E Ar regioselectivity rules can be readily accessed.

Recent Update on Transition Metal‐Free C(sp2)−H Bond Halogenation in (Hetero) Arenes

“…Protecting group controlled remote C(sp 2 -H) iodination was reported by Brittain and Cobb in arene systems (Scheme 34). [46] In their protocol, tetrafluoropyridyl (TFP) group was used to protect a phenolic À OH group present in the substrate (53). The said protecting group controls the regioselctivity of the iodination resulting in iodinesubstitution at a position not easily accessible by classical electrophilic substitution.…”

“…[hmim]Br DCDPH,NBS Chiral Organocatalyst [56] K 2 S 2 O 8 TBAX or NXS [85] (Cl/Br/I) Electrochemical [74] Acyl chloride [91] NXS (X=Br/Cl/I) AlCl 3 /NXS PIDA (X=Br/Cl) NIS,TFA [46] ArI(OAc) 2 [43] PIDA/NaX [76] (X=Cl/Br/I) NaX NFSI [92] (X=Br/I) NaI,Electrolysis [101] TBAB or TBAC [52] (Pummerer) Erythrosin B, NBS,LED [22] PhI(OAc) 2 or K 2 S 2 O 8 NaBr [38] TXCA [102] ChemistrySelect material in case of mono C-5 halogenation in presence of TEMPO possibly indicated that the NXS was being captured by TEMPO preventing subsequent halogenation. N-flurobenzenesulfonimide (NFSI) was used as an oxidant and sodium salts of halogens (bromine and iodine) acted as halogen source for the halogenation of quinolines (137)and arenes.…”

Synthesis of complex unnatural fluorine-containing amino acids

“…This amino acid was shown to be readily incorporated into peptides, and further it was disclosed that through the addition of a thiol and a fluoride source, the TFP group could be easily removed to give free phenolic tyrosine. The TFP ring was also shown to have profound electronic implications [ 72 , 73 ].

Scheme 14 Synthesis of tetrafluoropyridyl amino acids, Cobb and co-workers [ 70 , 72 ].

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Iodinated Diketopiperazines: Synthesis and Biological Evaluation of Iodinated Analogues of Cyclo(L‐Tyrosine‐L‐Tyrosine) Peptides

“…Halo-arene synthesis by EAS strategy is an essential guiding reaction for understanding the reactivity and functionalization of aromatics. [6][7][8] Halo-arenes frequently occur in pharmaceuticals and agrochemicals as essential functional molecule [9] (Scheme 1B). Therefore, halogenated aromatic amino acids represent an important class of building blocks, which have been utilized for various applications.…”

“…ortho to the phenolic hydroxyl group in tyrosine to yield the formation of thyroxine [2–5] (Scheme 1A). Halo‐arene synthesis by EAS strategy is an essential guiding reaction for understanding the reactivity and functionalization of aromatics [6–8] . Halo‐arenes frequently occur in pharmaceuticals and agrochemicals as essential functional molecule [9] (Scheme 1B).…”